A novel class of lipid formulation was investigated comprising GRAS (generally
regarded as safe) materials. The formulations were all ‘surfactant-free’ (S-F)
formulations, and also referred to as ‘Type IV’ lipid formulations. These
formulations were isotropic, transparent, thermodynamically stable at room
temperature and typically composed of > 50 % of mixed mono-, di- and triglycerides,
> 30 % medium chain fatty acids oil and < 20 % hydrophilic co-solvent.
At equilibrium, S-F formulations enhanced the solvent capacity of corticosteroids
(log P > 3) and hydroxy benzoate derivatives over type II SEDDS and type III
SEDDS, but generally were not superior solvents to mixtures of mono-, di- and triglycerides
(Imwitor 988® and or Capmul MCM®) alone, for lipophilic steroids (log
P < 3). In general, type III SEDDS which were composed of high hydrophilic
content (hydrophilic surfactant, HLB > 1 2 , and hydrophilic co-solvent), were also
better solvents for most steroidal compounds and hydroxy benzoate derivatives than
type II SEDDS and type I SEDDS formulations.
Surfactant with HLB > 12 inhibited lipolysis of MCT and mixed glycerides when the
concentration of surfactant exceeded 40 % w/w. Hydrophobic surfactants (HLB < 10)
did not inhibit lipolysis. Thus, the digestibility of dispersions formed by selfemulsifying
systems would be dependent on the surfactants used and the quantity of
TG available for lipolysis. Co-solvents did not appear to influence lipolysis, once the
formulations had dispersed.
Phase separation of lipid formulations following their dispersion in simulated
intestinal fluid was studied. The lipid formulation behaviour was dependent on
monoglyceride content. When sufficient monoglyceride (> 60 %w/v) was present
demulsification and phase separation was noticed and was found to be dependent on
the presence of phospholipid. This resulted in sedimentation of the phase rich
monoglyceride and water. The presence of triglyceride stabilised the formation of
mixed micelles, which remained in a finely dispersed state. This unexpected phase
separation is likely to have a considerable effect on the fate of drug dissolved in
SEDDS formulations. The high concentrations of monoglyceride may be
disadvantageous and could possibly result in precipitation of drug.
|Date of Award||20 Nov 2002|
|Supervisor||Colin Pouton (Supervisor)|